In this project, our group is examining biological aspects of risk for mood and anxiety disorders in children. Such work has major public impact. By identifying biological risks in children, information on novel treatments and preventative interventions will emerge. Given the understanding of most chronic mental illnesses as developmental disorders, such information holds the hope of dramatically influencing the mental well-being of many individuals. This project encompasses work that is being implemented in three protocols. In one protocol, we are examining the degree to which traumatic experiences predict perturbations in brain function among youth with or without mood or anxiety disorders. In a second protocol, we are examining neurocognitive profiles in a cohort of approximately 350 children and adolescents stratified with respect to personal and family history of mood and anxiety disorders. In a third protocol, we are acquiring fMRI data from a subset of these 350 subjects. Considerable progress has been made during the first five years of work covered in this protocol. However, the amount of work being performed in this protocol has slowed during each of the past two years. The trend continues during the past year. This trend applies both to his protocol specifically over time as well as relative to work being performed in other protocols. This continued trend is because studies of family-risk are quite resource intensive, and insufficient resources are available to maintain all of the ongoing studies on risk. Studies on temperamental risk generally have received more resources than those of family-risk. This trend has also continued, as reflected in research on other protocols performed by the research group. Major questions remain on family-based associations, concerning the degree to which these associations reflect environmental, genetic, or interacting influences of genes and the environment. Moreover, other questions relate to the identification of factors that differentiate among children who are at high risk yet remain resilient from those who are at risk but manifest problems. Work in this project over the next few years is designed to address these questions. Adults with post-traumatic stress disorder (PTSD) or major depressive disorder (MDD) exhibit abnormalities in the structure and function of the amygdala, prefrontal cortex (PFC), and hippocampus. However, while these psychiatric disorders often emerge in childhood, the integrity of these neural structures have been minimally studied in psychiatrically impaired children and adolescents. Work performed in the current protocol has already begun to show that biological correlates of adult mental disorders may manifest quite early in life. In the current proposal on trauma, functional MRI (fMRI) will be used to evaluate the amygdala and the hippocampus in 1) healthy adolescents and those with the following conditions: 2) PTSD;3) MDD;4) PTSD and MDD;and 5) abuse without PTSD or MDD. This aspect of the project is actually proceeding relatively slowly. Our group has been able to acquire some data on PTSD and on MDD. We have also published a series of papers on these issues. However, recruitment is generally slow, and we still have yet to demonstrate clear and consistent findings differentiating cognitive and neural functioning in these two groups. Our plan for the coming year is to focus our efforts specifically on studies of temperament, as a risk factor, more than our studies specifically among traumatized indivdiuals. Because we do comprehensively assess stress exposure in all subjects, our studies of temperament should generate insights on the effects of stress in children. Anxiety in children of parents with major depressive disorder (MDD) poses a particularly high risk for later-life MDD. In adults, MDD involves dysfunction in prefrontal brain regions that regulate attention to emotional stimuli. These abnormalities: i) have been found primarily in adults with specific familial forms of MDD;ii) persist after recovery from MDD, and iii) relate to anxiety. These findings raise the possibility that risk for MDD is tied to dysfunction in prefrontal regions involved in regulation of emotion, which possibly manifests as early-life anxiety. If this possibility were confirmed in never-depressed adolescents at high risk for MDD, the findings would provide key insights into the developmental neurobiology of MDD. The goal of this protocol is to study the neural substrate of risk for MDD in young people. This protocol tests the hypothesis that adolescents at high risk for MDD by virtue of childhood anxiety and parental history of MDD exhibit dysfunction in prefrontal cortex and amygdala, regions involved in emotion regulation. This goal will be accomplished through behavioral and fMRI studies of emotion regulation in high and low-risk adolescents. In contrast to our work on trauma, we have made considerable progress in this area. This progress is reflected in a serious of high-impact publications emerging from this work. With respect to our research neurocognitive profiles in offspring of depressed and/or anxious parents, we have acquired data in 225 subjects, working closely with a group from New York University Child Study Center. This includes behavioral data on a face-viewing paradigm that we have also been using to conduct our fMRI studies. Finally, we also continue to maintain a strong collaborative relationship with Dr. Nathan Fox at the University of Maryland. More than the other areas of risk in the current set of studies, these studies with Dr. Fox have received very high priority. Dr. Fox has followed cohorts of approximately 600 infants as they passed though childhood. These children have received repeated assessments of their temperament. Temperament classifications in the sample during infancy and early childhood have been shown to predict behavior later in life. We have also completed an ever-increasing series of investigations in this sample. Results from these studies support the conclusions generated in other research within our group. Namely, this work establishes the presence of strong, consistent associations between the presence of and risk factors for mental illness in children and the presence of perturbed brain function.